Luminal prostheses and methods for coating thereof

ABSTRACT

Luminal prostheses comprise scaffolds having coatings adhered to at least a portion of their outer surfaces. The surfaces are modified to enhance binding of the coatings. For example, the surfaces may be microblasted, laser treated, chemically etched, exposed to plasma, or exposed to a corona discharge, allowing a polymeric coating to adhere to the scaffold more tightly than in the absence of the surface modification. The coatings can be used to deliver therapeutic or other agents dispersed therein.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/426,598 (Attorney Docket No. 32016-705.501), filed Apr. 20,2009, now U.S. Pat. No. ______, which is a continuation-in-part of U.S.Patent Application No. PCT/US07/81996 (Attorney Docket No.32016-705.601), filed Oct. 19, 2007, which claims priority to U.S.Provisional Patent Application No. 60/862,250 (Attorney Docket No.32016-705.101), filed Oct. 20, 2006, the disclosures of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates generally to medical devices and methodsfor their preparation. More particularly, the present invention relatesto luminal prostheses having polymer coatings and methods for theirpreparation.

Luminal prostheses are used for maintaining patency in various bodylumens, most notably in the vasculature and the ureter. The most commonform of luminal prosthesis is referred to as a “stent,” which is agenerally tubular-shaped scaffold which is deployed to hold open orreinforce a segment of a body lumen. Stents are most commonly used inthe vasculature where they are deployed in the coronary arteries, thecarotid artery, the femoral artery, as well as in the peripheralarterial and venous vasculature. Stents and other luminal prostheses,however, also find use for treating aortic aneurysms, thoracicaneurysms, for supporting bioprosthetic valves, and for other purposes.

Stents are typically delivered to a target region within a body lumenusing a catheter. Balloon-expandable stents are commonly mounted on aballoon catheter, navigated to the target region, and expanded byinflating the balloon. Self-expanding stents are most often delivered toa target region while constrained in a sheath or other tubular member.Once they reach the target region, the constraint can be removed and thestent will expand and deploy within the body lumen.

Stents and other luminal prostheses may also be modified to carry andelute drugs and pharmaceutical agents within a body lumen for a varietyof purposes. Within the vasculature, the drugs and pharmaceutical agentsare typically intended to reduce tissue inflammation, restenosis, orthrombosis, and/or to promote healing and biocompatibility of thedevice. Of particular interest to the present invention, drugs and otherpharmaceutical agents are often eluted from a polymer matrix which hasbeen coated over at least a portion of the stent surface. To beeffective, the polymer should be able to accommodate stent preparationand processing as well as subsequent expansion within the vasculature orother body lumen. In particular, the coatings should suffer minimal orno cracking or smearing which can result from deformation and strain asthe stent is crimped, expanded, or otherwise deformed during processingof delivery.

For these reasons, it would be desirable to provide improved coatedprostheses, catheters for delivering such coated prostheses, and methodsfor fabricating such coated prostheses. In particular, the coatings onthe prostheses should resist cracking and smearing during fabrication,preparation, and delivery to a targeted body lumen. The deliverycatheters should further help reduce cracking and smearing duringdelivery. Finally, the fabrication methods should apply the coatings tothe prostheses in a manner which promotes coatings which resist crackingand smearing. At least some of these objectives will be met by theinventions described below.

2. Description of the Background Art

The following U.S. patents and printed publications describe luminalprostheses and other implantable devices having polymer and othercoatings for drug delivery and other purposes: U.S. Pat. Nos. 7,232,573;7,163,555; 7,055,237; 7,008,979; 6,984,393; 6,918,929; 6,855,770;6,824,559; 6,712,846; 6,653,426; 6,592,895; 6,653,426; 6,224,894;6,153,252; and 6,120,847; and U.S. Publication Nos. 2007/0207184;2007/0185569; 2007/0168012; 2007/0123973; 2007/0106371; 2007/0073016;2007/0003592; 2006/0282166; 2006/0257355; 2006/0212106; 2006/0198868;2006/0093771; 2006/0067908; and 2005/0271700.

SUMMARY OF THE INVENTION

The present invention provides luminal prostheses, catheter assembliesfor delivering such prostheses, and methods for fabricating suchprostheses. The luminal prostheses comprise a scaffold having a modifiedsurface region which has a coating comprising a material which interactswith the modified surface region to provide an adherence of the coatingto the surface greater than an adherence in the absence of the surfacemodification. The luminal prostheses comprise a scaffold having amodified surface region which has a coating comprising a material whichsoftens in a physiologic environment and interacts with the modifiedsurface region to provide an adherence of the coating to the surfacegreater than an adherence in the absence of the surface modification.The coating will typically comprise a polymer, as discussed below, butcould also comprise proteins, peptides, extracellular matrix, metals,metal alloys, ceramics, and the like, and will often carry a therapeuticor other agent dispersed, distributed within the coating, or adjacent tothe coating and intended to be released from the coating in aphysiologic environment.

The scaffold will typically be in the form of a luminal stent, moretypically being a stent intended for implantation within a patient'svasculature for treating regions of coronary artery or other vasculardisease. Most commonly, the stents will be formed from a metal. Metalstents may either be balloon-expandable or self-expanding. The mostcommon balloon-expandable stents are formed from stainless steel orcobalt-chromium alloys. Self-expanding stents are most commonly formedfrom nickel-titanium alloys or, in some cases, spring stainless steels.In addition to metal stents, the scaffolds of the present invention maybe formed from polymeric materials, including both balloon-expandable(malleable) polymers and resilient polymers which could be used forpreparing self-expanding scaffolds. Particular examples of stentpatterns and stent materials are provided hereinafter.

Preferred coating materials comprise polymers having a glass transitiontemperature below physiologic temperature (37° C.). Such polymers may benon-erodible or erodible (biodegradable within the vascular or otherluminal environment). Suitable erodible or biodegradable polymers willtypically have a molecular weight above 50 KDa, usually over 150 KDa,and often over 200 KDa. Such erodible or biodegradable coatings may havewidely varying times for degrading. For example, it may be desirable toemploy polymers which degrade relatively rapidly, for example over atime period of less than six months, often less than three months, andin preferred embodiments, less than one month. Biodegradable polymerssuitable for use in the present invention include poly(alkene carbonate)polymers, copolymers of poly(lactide) and trimethylene carbonate,copolymers of poly(lactide) and poly(glycolide), and copolymers ofpoly(lactide) and polyethylene glycol family of polymers. A preferredbiodegradable polymer is polyethylene carbonate (PEC) having a molecularweight of 150 KDa or greater, which will substantially degrade whenpresent in the vascular environment in less than six months, often lessthan three months, and usually less than one month.

A second exemplary erodible polymer comprises a copolymer ofpoly-L-lactide and trimethylene carbonate (PLLA:TMC). The molarpercentage of PLLA in PLLA:TMC can range from 50% PLLA to 95% PLLA,which polymer coating degrades substantially in less than 4 years, morepreferably less than 2 years, most preferably less than 1 year.

In another embodiment, the erodible polymer coating comprises acopolymer of poly-L-lactide and poly glycolic acid (PLLA:GA). The molarpercentage of PLLA in PLLA:GA can range from 50% PLLA to 95% PLLA.

In another embodiment, the erodible polymer coating comprises acopolymer of poly lactide and polyethylene glycol (PLA:PEG). The molarpercentage of PLA in PLA:PEG can range from 50% PLA to 99% PLA, whichpolymer coating degrades in less than 2 years, more preferably less than1 year, most preferably less than 9 months.

Exemplary non erodible polymer compositions include poly(alkylmethacrylate) polymers. In a preferred embodiment the polymer is apoly-n-butylmethacrylate (PBMA). The non erodible polymers typicallyhave molecular weight greater than 500 KDa, and an exemplary PBMA stentcoating has a molecular weight greater than 700 KDa.

The polymer materials described above will usually be present in a pureor neat formulation with few or no additives or other materials, exceptfor the therapeutic or other agents which are being incorporated in anddelivered by the polymer coating. In other instances, however, thepolymers described above could be combined with other materials orpolymers for purposes known in the art. Such additional materialsinclude plasticizers, anti-oxidants, stabilizers, and the like.

The polymer or other coatings on the scaffold will typically have athickness in the range from 0.1 μm to 100 μm, preferably from 1 μm to 50μm, and more preferably from 3 μm to 10 μm. The amounts of polymercoating may range from a total of 10 μg to 5 mg, preferably from 25 μgto 1 mg, and more preferably from 100 mg to 500 mg.

The polymer coatings will typically include one or more therapeutic orother agents at a relatively high loading percentage. Typically, thetherapeutic or other agent will be present within the polymer in anamount greater than 30% of the total coating weight (including bothpolymer and therapeutic agent), more preferably being greater than 60%of the total coating weight, and most preferably being 65% of the totalcoating weight or greater. As mentioned above, other materials couldalso be included within the polymer coating, although the total loadingof non-polymer materials will desirably be kept within the weightpercentages set forth above.

The loading of therapeutic or other agent contained within the polymercan range from 1 ng/cm² to 1000 μg/cm², preferably 1 μg/cm to 500μg/cm², more preferably 10 μg/2 to 400 μg/cm², based on the area of thescaffold. The therapeutic or other agent is released from the polymercoating at rates ranging from 1 ng/cm²/day to 1000 μg/cm²/day,preferably 1 μg/cm²/day to 200 μg/cm²/day, more preferably from 5μg/cm²/day to 100 μg/cm²/day. The therapeutic agent uptake in the tissueadjacent to the polymer coated stent can range from 0.001 ng/gm tissueto 1000 μg/gm tissue, preferably 1 ng/gm tissue to 100 μg/gm tissue,more preferably 100 ng/gm tissue to 50 μg/gm tissue. The therapeuticagent is usually released substantially completely from the prosthesisover a time ranging from 1 day to 6 months, preferably from 1 week to 3months, more preferably from 2 weeks to 6 weeks. Release of thetherapeutic or other agent from a non-erodible stent will typicallydepend on the nature of the pore structure or other reservoir formedwithin the polymer matrix. In the case of erodible stents, thetherapeutic or other agent may be similarly released through a networkof pores or other reservoir structure prior to eroding of the polymer.In other cases, however, release of the therapeutic agent may occur atleast partly as a result of the polymer eroding over time.

Exemplary therapeutic agents that may be carried in the polymericcoating include immunomodulators, anti-cancer, anti-proliferative,anti-inflammatory, antithrombotic, antiplatelet, antifungal,antidiabetic, antihyperlipidimia, antiangiogenic, angiogenic,antihypertensive, or other therapeutic classes of drugs or combinationthereof.

For example, immunomodulators agents includes but not limited torapamycin, everolimus, Novolimus, ABT 578, AP20840, AP23841, AP23573,CCI-779, deuterated rapamycin, TAFA93, tacrolimus, cyclosporine, TKB662,myriocin, their analogues, pro-drug, salts, or others or combinationthereof.

Illustrative anticancer agents include acivicin, aclarubicin, acodazole,acronycine, adozelesin, alanosine, aldesleukin, allopurinol sodium,altretamine, aminoglutethimide, amonafide, ampligen, amsacrine,androgens, anguidine, aphidicolin glycinate, asaley, asparaginase,5-azacitidine, azathioprine, Bacillus calmette-guerin (BCG), Baker'sAntifol (soluble), beta-2′-deoxythioguanosine, bisantrene HCl, bleomycinsulfate, busulfan, buthionine sulfoximine, BWA 773U82, BW 502U83.HCl, BW7U85 mesylate, ceracemide, carbetimer, carboplatin, carmustine,chlorambucil, chloroquinoxaline-sulfonamide, chlorozotocin, chromomycinA3, cisplatin, cladribine, corticosteroids, Corynebacterium parvum,CPT-11, crisnatol, cyclocytidine, cyclophosphamide, cytarabine,cytembena, dabis maleate, dacarbazine, dactinomycin, daunorubicin HCl,deazauridine, dexrazoxane, dianhydrogalactitol, diaziquone,dibromodulcitol, didemnin B, diethyldithiocarbamate, diglycoaldehyde,dihydro-5-azacytidine, doxorubicin, echinomycin, edatrexate, edelfosine,eflomithine, Elliott's solution, elsamitrucin, epirubicin, esorubicin,estramustine phosphate, estrogens, etanidazole, ethiofos, etoposide,fadrazole, fazarabine, fenretinide, filgrastim, finasteride, flavoneacetic acid, floxuridine, fludarabine phosphate, 5-fluorouracil,Fluosol®., flutamide, gallium nitrate, gemcitabine, goserelin acetate,hepsulfam, hexamethylene bisacetamide, homoharringtonine, hydrazinesulfate, 4-hydroxyandrostenedione, hydrozyurea, idarubicin HCl,ifosfamide, interferon alfa, interferon beta, interferon gamma,interleukin-1 alpha and beta, interleukin-3, interleukin-4,interleukin-6,4-ipomeanol, iproplatin, isotretinoin, leucovorin calcium,leuprolide acetate, levamisole, liposomal daunorubicin, liposomeencapsulated doxorubicin, lomustine, lonidamine, maytansine,mechlorethamine hydrochloride, melphalan, menogaril, merbarone,6-mercaptopurine, mesna, methanol extraction residue of Bacilluscalmette-guerin, methotrexate, N-methylformamide, mifepristone,mitoguazone, mitomycin-C, mitotane, mitoxantrone hydrochloride,monocyte/macrophage colony-stimulating factor, nabilone, nafoxidine,neocarzinostatin, octreotide acetate, ormaplatin, oxaliplatin,paclitaxel, pala, pentostatin, piperazinedione, pipobroman, pirarubicin,piritrexim, piroxantrone hydrochloride, PIXY-321, plicamycin, porfimersodium, prednimustine, procarbazine, progestins, pyrazofurin, razoxane,reveromycin, sargramostim, semustine, spirogermanium, spiromustine,streptonigrin, streptozocin, sulofenur, suramin sodium, tamoxifen,taxotere, tegafur, teniposide, terephthalamidine, teroxirone,thioguanine, thiotepa, thymidine injection, tiazofurin, topotecan,toremifene, tretinoin, trifluoperazine hydrochloride, trifluridine,trimetrexate, tumor necrosis factor, uracil mustard, vinblastinesulfate, vincristine sulfate, vindesine, vinorelbine, vinzolidine, Yoshi864, zorubicin, QP-2, epothilone D, epothilone C Taxol, such as,paclitaxel, docetaxel, ABJ879, patupilone, MN-029, BMS247550,ecteinascidins such as ET-743, tetrahydroisoquinoline alkaloid,sirolimus, actinomycin, methotrexate, antiopeptin, vincristine,mitomycin, 2-chlorodeoxyadenosine or others, antifungal agents such ascaspofungin, farnesylated dibenzodiazepinone, ECO-4601, fluconazole, orothers, angiogenesis drugs such as follistatin, leptin, midkine,angiogenin, angiopoietin-1, becaplermin, Regranex, anti-angiogenesisdrugs such as canstatin, angiostatin, endostatin, retinoids, tumistatin,vasculostatin, angioarrestin, vasostatin, bevacizumab, prinomastat, orothers, antidiabetic drugs such as metformin, hypertension drugs such ascandesartan, diovan, diltiazem, atenolol, adalat or others,anti-ischemia drugs such as ranolazine, isosorbide dinitrate, or others.

Illustrative antiinflammatory agents include classic non-steroidalanti-inflammatory drugs (NSAIDS), such as aspirin, diclofenac,indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen,piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid,fenoprofen, nambumetone (relafen), acetaminophen (Tylenol®), andmixtures thereof; COX-2 inhibitors, such as nimesulide, NS-398,flosulid, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxibsodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067, L-748780,L-761066, APHS, etodolac, meloxicam, S-2474, and mixtures thereof;glucocorticoids, such as hydrocortisone, cortisone, prednisone,prednisolone, methylprednisolone, meprednisone, triamcinolone,paramethasone, fluprednisolone, betamethasone, dexamethasone,fludrocortisone, desoxycorticosterone, fluticasone propionate,piroxicam, celeoxib, mefenamic acid, tramadol, meloxicam, methylprednisone, pseudopterosin, or others, hypercalcemia drugs such aszoledronic acid, alendronate or others, antithrombosis drugs likeplavix, heparin, Arixtra and Fraxiparine or others or mixtures thereof.

Therapeutic agents also include analogues, prodrugs, derivatives,precursors, fragments, salts, or other modifications or variations ofpharmaceutical agents listed above. In another embodiment, the coatingcontains endothelial cell adhesion and/or growth promoting agent such aspeptides such as RGD peptide sequence, extracellular matrix such asheparin sulphates, chondroitin sulphate, proteins such as fibronectin,fibrinogen, albumin or others. In one embodiment, the coating is applieddirectly on the surface of the prosthesis. In another embodiment, thecoating is distributed or dispersed within a polymer and/or therapeuticagent. In one embodiment, an endothelial cell adhesion and/or growthpromoting agent is attached to the prosthesis. In another embodiment,the endothelial cell adhesion and/or growth promoting agent is releasedfrom the prosthesis after implantation over time. The agent can bereleased from the prosthesis over a period in the range from 6 hr to 7days, preferably from 7 days to 30 days, most preferably from 30 days to6 months. In another embodiment, the endothelial cell adhesion and/orgrowth promoting agent is applied as topcoat to the polymer and/ortherapeutic agent. The coating thickness is less than 5 μm, preferablyless than 1 μm, most preferably less than 0.1 μm. The coating can besprayed, dip coated, brushed, dispensed or by other means.

The present invention also provides catheter assemblies comprising acatheter having an expandable polymeric balloon, typically located neara distal end of a catheter body. A luminal prosthesis is carried on theexpandable balloon, and the prosthesis generally comprises a scaffoldand a coating formed over a modified region in the scaffold, asdescribed in detail above.

In yet another aspect of the present invention, a luminal scaffold maybe coated with a material by modifying at least a portion of a surfaceregion of the scaffold and coating the material over the modifiedsurface region. The modification is performed in order to increase theadherence of the polymer coating, and the coating and the modifiedsurface will interact to have an adherence greater than the adherence inthe absence of the surface modification. The luminal scaffolds andexemplary polymers may be the same as described above in connection withthe structure of the luminal prosthesis itself. The surface modificationmay be any one of a variety of treatments intended to promote theadhesion of polymer coatings on a targeted region of the scaffoldsurface. In particular, it is desired that the adhesion be sufficient toprevent or minimize coating from cracking or smearing during stentcrimping during processing or expansion during deployment. Surfacetexturing is a preferred modification which can be achieved throughvarious methods, including micro-blasting, laser treatment, chemicaletching, plasma exposure, or corona exposure. The surface modificationsmay be complete, partial or selective to cover all or portions of theexposed surfaces of the scaffold.

As a particular example, a microblast modified surface may provideround, trenches, regular or irregular shaped features. The averagefeature size (maximum length, diameter, or width) can vary preferablyfrom 50 nm to 50 μm, more preferable 1 μm to 10 μm, and most preferably5 μm to 10 μm. The average depth of the features can vary preferablyfrom 50 nm to 50 μm, more preferable 1 μm to 10 μm, and most preferably5 μm to 10 μm. The average density of features is preferably 0.001 to0.10 features per μm², more preferably 0.003 to 0.05 features per μm²,and most preferably 0.005 to 0.02 features per μm². The average size ofblasting media for micro-blasting is preferably 5 μm to 100 μm, morepreferably between 20 μm to 50 μm. The type of blasting media can bemade from aluminum oxide, glass, metal, or other known in the art.

The stent surface modification enables polymer coating compositioncontaining high percentage of therapeutic agents to be crimped orexpanded with minimal or no cracking or smearing. In one embodiment, thepercentage of therapeutic agent in the polymer composition may equal toor greater than about 40%, preferably equal to or greater than 65%, andmore preferably equal to or greater than about 80%, while stillmaintaining an adherence greater than in the absence of surfacemodification.

After the surface region of the scaffold has been modified as describedabove, the polymer will be applied, typically together with thetherapeutic or other agent. The polymer and the therapeutic or otheragent are usually dissolved in one or more solvents prior to applyingthe coating on the stent surface. Typically, the choice of solvents isbased on the solubility of the polymer and therapeutic agent. Thesolvent is preferably selected to have additional properties whichminimize or eliminate cracking or smearing or promote adhesion of thecoating to the stent upon crimping or expansion.

Residual solvents in polymer coatings on a stent can adversely impactcoating cracking or smearing. It has been found by the inventors hereinthat solvents with low boiling points, high evaporation rates, lowviscosities and/or high vapor pressures minimize residual solvents inpolymer coating. By properly choosing the solvent, the residual solventin the polymer will be less than 10000 ppm, preferably less than 5000ppm, and more preferably less than 1000 ppm after stent coating. Thesolvent used for dissolving the coating preferably has a relativeevaporation rate of 10 or higher (as compared to a rate of 1 for n-butylacetate). The solvent preferably will also have a boiling point of 60°C. or lower. Further, the solvent will preferably have a vapor pressureof 50 mmHg or higher at 20° C. Still further, the solvent willpreferably have a viscosity of 1 cP or lower at 25° C.

A solvent with low surface tension with the stent material is preferredto increase wetting the stent surface with coating and increasing theadhesion of the coating to the modified surface of the stent. Thesolvent will preferably have a surface tension of less than 70 dyne/cm,preferably less than 50 dyne/cm, more preferably less than 30 dyne/cm.

An empirical formula devised by the inventors herein can be used todetermine which solvent best meets the requirement for dissolving thecoating into a solution and using the solution to apply the coating ontothe stent with a minimum residual solvent. The coating solvent index iscalculated using the following formula:

${{Coating}\mspace{14mu} {Solvent}\mspace{14mu} {Index}\mspace{14mu} {Value}} = \frac{\begin{matrix}{{Evaporation}\mspace{14mu} {Rate} \times} \\{{Vapor}\mspace{14mu} {Pressure}}\end{matrix}}{\begin{matrix}{{Boiling}\mspace{14mu} {Point} \times {Viscosity} \times} \\{{Surface}\mspace{14mu} {Tension}}\end{matrix}}$

The properties and index of some typical solvents are provided in Table1 below.

TABLE 1 Coating Vapor Solvent Pressure Surface Index Boiling @ ViscosityTension (Evap × Evaporation Point @ 20° C./ (cP or (dynes/cm Vapor/ Rate(n- 760 mmHg 68° F. mPa · s @ @ 25° C./ (BP × Visc × Chemical Name BuAc= 1) (° C.) (mmHg) 25° C.) 77° F.) Surf Ten) Diethylene glycol butyl 0.2242 0.01 3.2 30 0.00 ether acetate Tripropylene glycol 0.2 236 0.03 6.029 0.00 methyl ether Tripropylene glycol 1 274 0.01 8.0 30 0.00 normalbutyl ether Diethylene glycol butyl 0.3 230 0.06 4.7 30 0.00 etherDipropylene glycol 1 229 0.02 4.8 29 0.00 normal butyl ether Propylenecarbonate 0.5 242 0.03 2.4 41 0.00 N-methyl-2-pyrrolidone 0.03 202 0.291.7 40 0.00 Dipropylene glycol 1.3 212 0.05 4.4 26 0.00 normal propylether Dipropylene glycol 1 200 0.05 2.2 28 0.00 methyl ether acetateEthylene glycol butyl 3 190 0.02 1.8 30 0.00 ether acetate Diethyleneglycol ethyl 2 198 0.12 4.5 32 0.00 ether Diethylene glycol methyl 2 1940.2 3.9 35 0.00 ether Dipropylene glycol 2 180 0.17 4.0 28 0.00 methylether Ethylene glycol butyl 6 169 0.6 6.4 27 0.00 ether Propylene glycolnormal 7 170 0.62 3.5 26 0.00 butyl ether Propylene glycol methyl 19 1570.9 1.1 34 0.00 ether propionate Propylene glycol normal 22 150 1.7 2.327 0.00 propyl ether Propylene glycol tertiary 30 151 2.81 4.0 24 0.01butyl ether Isopropanol 1.7 80 32 2.86 23 0.01 Propylene glycol methyl34 140 2.8 1.1 27 0.02 ether acetate Propylene glycol ethyl 44 132 101.8 30 0.06 ether Propylene glycol methyl 70 120 8.1 2.0 27 0.09 etherMethanol 3.5 65 97 0.59 23 0.38 Tertiary butyl alcohol 95 82 31 3.3 200.54 Tetrahydrofuran 8 66 129 0.5 26 1.20 Chloroform 11.6 62 142 0.54227 1.82 Acetone 5.6 56 184.5 0.32 25 2.31 Diethylamine 6.9 56 195 0.3420 3.53 Ethanol 170 78 43 1.1 22 3.87 Tertiary butyl acetate 280 98 31 122 4.03 Dielholormethane 27.5 40 350 0.44 27 20.25 Diethyl ether 37.5 35442 0.22 72.8 29.57 Trichlorofluormethane 63 24 803 0.43 18 272.34Methyl tertiary butyl 814 55 204 0.3 19 529.68 ether

The invention claims the use of a solvent with coating solvent indexgreater than 1, preferably greater than 10 and more preferably greaterthan 20.

After the luminal prosthesis has been prepared as described above, itwill be loaded onto a delivery catheter. In the case ofballoon-expandable prostheses, the balloon catheter will have aninflatable balloon, typically formed from a polymer, more typically anon-distensible polymer. The scaffold of the prosthesis will typicallybe crimp mounted on the balloon, and the stent and balloon thereafterplaced in a polymer sheath and heated under high pressure. Suchconventional heat treatment helps embed the scaffold into the deliveryballoon with portions of the balloon “pillowing” into the intersticesbetween the stent elements. As the heat setting has previously had atendency to cause cracking or smearing in the polymeric coatings, it hasbeen found that using balloons having a glass transition temperaturelower than that of the coating polymer allows heat treatment attemperatures below those which would adversely impact the coatingpolymer material.

In yet another aspect of the present invention, a particular scaffoldstructure that is designed to minimize surface stresses during crimpingand expansion is provided. The luminal scaffold comprises a plurality ofaxially joined serpentine rings having struts joined by crowns. Thecrowns on opposed adjacent rings are connected by straight connectorlinks, where the connectors between successive pairs of adjacent ringsare angled in opposite directions relative to an axial direction. Inpreferred embodiments, the connectors are disposed at angles in therange from 40° to 60° relative to the axial direction. The scaffoldtypically includes from six to 12 crowns, and from two to fourdiametrically opposed connectors between each pair of adjacent rings.The connectors usually have a length in the range from about 0.025 mm to2.5 mm, and the crowns are rotationally offset in the range from 5° to75° and axially separated by a distance in the range from 0.25 mm to 0.1mm. Typically, the width and/or thickness of the connectors is less thanthe width and/or thickness of the crowns. In this way, the crowns willusually have a strain of 50% or less at the maximum radial expansion ofthe scaffold.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 1A and 2 illustrate an exemplary scaffold structure constructedin accordance with the principles of the present invention, with thestent and a catheter shown in FIG. 1A.

FIG. 3 is an SEM image of the outside of a luminal scaffold prepared asdescribed in Example 1.

FIG. 4 is an SEM image showing the surface features of the scaffoldprepared in Example 3.

FIG. 5 is a light microscope image of the inside of the stent preparedin Example 5 after mounting and expansion as described in Example 7.

FIG. 6 is a light microscope image of the outside diameter of the stentdescribed in Example 7.

FIG. 7 is a chart comparing the neointimal area of stents coated withPEC and PBMA in comparison to a bare metal stent after 28 days ofimplantation in a porcine coronary artery model, as described in Example8.

FIG. 8 is similar to FIG. 7, showing the results after 90 days ofimplantation.

FIG. 9 compares the neointimal area achieved with PEC drug coated stentswith that achieved in a Rapamycin eluting Cypher™ stent after 28 days ofimplantation in a porcine coronary artery model, as described in Example9.

FIG. 10 is similar to FIG. 9 showing the results after 90 days ofimplantation.

FIG. 11 compares the neointimal area achieved with PEC coated stentswith that achieved by Rapamycin eluting Cypher™ stents after 180 days ofimplantation in a porcine coronary artery model.

FIG. 12 is a graph illustrating the percentage of release of PEC from acoated stent over time in a porcine coronary artery model.

FIG. 13 is a graph depicting tissue concentration of PEC achieved atdifferent time points in a porcine coronary artery model, as describedin Example 10.

FIG. 14 compares the neointimal area achieved with a PBMA coated stentwith that obtained with a Rapamycin eluting Cypher™ stent after 28 daysof implantation in a porcine coronary artery model, as described inExample 11.

FIG. 15 is similar to FIG. 14, showing the results after 90 days ofimplantation.

FIG. 16 is a graph illustrating the percentage of PBMA released from acoated stent in a porcine coronary artery model over time, as describedin Example 11.

FIG. 17 is a graph showing the tissue concentration of PBMA releasedfrom a coated stent over time in a porcine coronary artery model, asdescribed in Example 12.

FIG. 18 compares the neointimal area achieved with a PLLA-TMC coatedstent compared to a Rapamycin eluting Cypher™ stent after 28 days ofimplantation in a porcine coronary artery model, as described in Example12.

FIG. 19 is a graph illustrating the percentage of PLLA-TMC released froma coated stent in a porcine coronary artery model over time, asdescribed in Example 14.

FIG. 20 is a graph illustrating the tissue concentration of PLLA-TMCover time in a porcine coronary artery model, as described in Example12.

DETAILED DESCRIPTION OF THE INVENTION

An exemplary vascular scaffold that is designed to minimize stress,cracking, or smearing of a coating is illustrated in FIGS. 1 and 2. Thebase structure of the scaffold is a lattice-like framework formed from aseries of interconnected crowns 12 and struts 14 forming serpentinerings which are unit building blocks to form longer structures. Links 16between rings affect the flexibility of the scaffold. Links 16 betweenrings are usually connected at the outside tips of the crowns 12slightly offset from the centerline or peak of the crown, and orientedsuch that the next ring is offset from the previous ring allowing thecrowns to avoid contact with each other as the stent is flexed. Thisamount of offset is determined by the take-off angle. The inventionclaims take-off angle α of the link to be between 30° and 60°, morepreferably between 45° and 55°, as shown in FIG. 2.

FIG. 1 illustrates the preferred embodiment in the expanded state withtwo connectors 16 and eight crowns 12 that provide flexibility andsidebranch access. The rings are slightly offset to avoid crown-to-crowncontact to minimize strut-to-strut contact during crimping and flexionwhile maintaining sufficient scaffolding upon expansion. FIG. 2illustrates how the connectors are joined to the crowns slightly offsetfrom the peak of the crown 12 at a take-off angle of 50° and alternatein direction from ring to ring to minimize uneven expansion. The stent10 is shown on a balloon 20 of a balloon catheter 22 having a catheterbody 24 and a proximal inflation hub 26, in FIG. 1A.

The link length and shape can also influence the suitability of thescaffold as a coating platform. The link shape is preferably straight toavoid interference with crowns. Also, the link length is selected toprovide the minimum gap necessary to avoid interference contact betweencrowns during crimping and flexing, usually being from 0.025 mm to 2.5mm. A longer link between rings will result in a greater gap betweenrings in the crimped state. The axial gap between rings or crowns of acrimped stent ranges from of 0.025 mm to 0.5 mm, preferably between 0.05mm and 0.1 mm and more preferably 0.1 mm and 0.05 mm.

Another aspect of the present invention is to minimize the number oflinks to promote flexibility of the stent and provide adequate sidebranch access. The number of links can vary depending on the number ofcrowns of the stent. The number of links can be a multiple of the numberof crowns to minimize uneven expansion. For example, nine crown stentwould have three links, an eight crown stent two or four links, etc. Thegreater the number of crowns, the higher the scaffolding or coverage isat a given expanded diameter. For example eight crown stent with twolinks will provide superior scaffolding versus a six crown stent withtwo links of similar crown design at a given diameter. In a preferredembodiment, a stent design for 2.5-4.5 mm diameter expansion with two tofour links and six to 12 crowns. The preferred embodiment is a stentwith two links and eight crowns to cover the entire diameter range withone stent pattern.

Another aspect of the present invention is to minimize the width of thelinks to improve flexibility of the stent. The invention claims thewidth of the link to be thinner than the strut width of the crowns. Thepreferred embodiment has a strut width of 0.1 mm with link widthsranging from 0.05 mm to 0.075 mm wide. Thinner struts may be used whilemaintaining a link width to strut width ratio of 50% to 90%.

Another aspect of the present invention is to design the number andshape of crowns such that upon crimping to the desired diameter orflexing, the crowns do not touch each other and damage the coating onthe stent while provide sufficient scaffolding upon expansion. Fewercrowns typically allow for a smaller crimp diameter before contactbetween crowns. The shape of the crowns also influences the likelihoodof contact between crowns; a U-shaped crown formed from a tight radiuswill take up less space than a key-hole shaped crown with a largerradius. The invention claims an eight U-shaped crown stent with twolinks with a crimp diameter of less than 0.1 mm.

Finite element methods are commonly used to predict the strain inducedduring crimping or expansion of the stent. Lower strains help tominimize or eliminate coating cracking or smearing during crimping orexpansion. Different materials will cause a stent to expand differentlyand thus experience different peak strains at maximum diameter.

For example a 0.08 mm thick cobalt-chrome eight crown stent with abovedesign in FIGS. 1 and 2 resulted in less than 25% strain at maximumexpansion and resulted in no coating cracks. The invention claims stentgeometry with less than 50% peak strain, preferably less than 30% peakstrain, more preferably less than 25% peak strain.

Another aspect of the present invention is that upon expansion, therings are neither aligned in-phase or out of phase, so that the cellgeometry is designed to provide scaffolding and adequate side branchaccess. When the crown tips are aligned with each other tip-to-tip,scaffolding is not optimal. When the rings are in phase, side-branchaccess may be compromised. By offsetting the rings slightly, scaffoldingcan be optimized while also maintaining adequate side branch access.

Another aspect of the present invention is that the links 16 inclinedrelative to the axial direction are oriented in alternating directionsalong the length of the scaffold, such that expansion forces arebalanced and the scaffold expands evenly. Uneven or unbalanced expansioncan have undesired effects on coatings present on the surface of thescaffold, as localized high-strain areas are introduced. Balancing uponexpansion can be characterized using finite element methods andmeasuring the opening of each crown. The deviation or coefficient ofvariance between crown openings should be minimized. By alternating thedirection of the links along the length of the stent, the coefficient ofvariance between crown openings in the design of FIGS. 1 and 2 wasreduced from 8% to 3%. The invention can achieve a coefficient ofvariance between crown openings to be less than 5%.

Struts that are too thin relative to the width of the strut may have atendency to twist as the stent is expanded, causing the coating to crackor smear. The invention claims a ratio of strut thickness versus strutwidth to be 0.6 to 1.0. In another embodiment, the current stent designshave little or no twisting out of plane upon expansion.

The stent implant may be manufactured using various methods, such aschemical etching, chemical milling, laser cutting, stamping, EDM, wateret cutting, bending of wire, injection molding, and welding.

The stent material may start as wire, drawn tubing, co-drawn tubing formultiple layer stent constructions, flat sheet, or other forms. Thestent material itself may be considered permanent, such as 316Lstainless steel, cobalt-chromium alloy (L-605, MP35N), elgiloy, nitinolalloy, platinum, palladium, tantalum, or other alloys and polymers.Alternatively, biodegradable materials may also be used, such asmagnesium, zinc, or their alloys or polymers such as poly-L-lactic acid,polyglycolic acid, polycaprolactone, copolymers of polylactic acid andpolyethylene glycol and others.

It can be appreciated that all the various inventions and embodimentsincluded in this application can be used alone or in variouscombinations with each other.

Example 1 Stent Surface Texturing

A 3×18 mm stent was put on a wire mandrel and rotated at 200 rpm. Amicro-blaster with a 0.020″ (0.5 mn) diameter nozzle was turned on suchthat 20 μm diameter media exits. The nozzle is placed 1 inch from thestent and allows it to traverse along the stent axially at a rate of 2seconds per inch back and forth. It is allowed to microblast the stentfor a total of 5 cycles. The stent direction is reversed andmicro-blasting is repeated. The stent is then precrimped to a smallerinner diameter such as 0.036″ (0.91 mn). It can be appreciated that theparameters used for surface texturing may vary. In this texturingprocess, the OD has higher average feature density than the ID andsidewall surfaces. FIG. 3 shows an SEM image of surface feature of astent OD.

Example 2 Stent Surface Texturing

A 0.0500″ (1.25 mm) diameter and 2″ (5 cm) long hypotube is connected tothe nozzle of a micro-blaster (Comco Inc). The hypotube is inserted intothe lumen of a 3 mm×18 mm stent. The micro-blaster is turned on suchthat the 25 μm diameter media exits the end of the hypotube. The stentis then slowly removed from the hypotube which results in texturing theinner and at least some sidewall surfaces of the stent. Themicro-blaster is turned off. The hypotube is again inserted into thelumen of the stent but in the reverse direction. The micro-blaster isturned on such that the 25 μm diameter media exits the end of thehypotube. The stent is then slowly removed from the hypotube whichresults in texturing the inner and at least some sidewall surfaces ofthe stent. The stent is then precrimped to a smaller inner diameter suchas 0.036″ (0.91 mn). It can be appreciated that the parameters used forsurface texturing may vary.

Example 3 Stent Surface Texturing

The stent from example 2 undergoes further surface modification prior toprecrimping to a smaller inner diameter. The stent is put on a wiremandrel and rotated at 200 rpm. A micro-blaster with a 0.020″ (0.5 mn)diameter nozzle is turned on such that 20 μm diameter media exits. Thenozzle is placed 1 inch from the stent and allows it to traverse alongthe stent axially at a rate of 2 seconds per inch back and forth. It isallowed to micro-blast the stent for a total of 5 cycles. The stentdirection is reversed and micro-blasting is repeated. The stent is thenprecrimped to a smaller inner diameter such as 0.036″ (0.91 mn). It canbe appreciated that the parameters used for surface texturing may vary.FIG. 4 shows an SEM image of surface feature of a stent ID.

Example 4 Stent With PBMA Coating

A 0.011″ (0.27 mn) wire mandrel is bent 360 degrees forming a loop atthe apex. It is inserted into a surface treated stent from example 3which was precrimped to 0.036″ (0.91 mn) ID. The mandrel is thenattached to the sample holding fixture of Sono-Tek Micromist™ ultrasoniccoater such that the stent is rotated and moving back and forth beneathan ultrasonic nozzle. The coater has syringe pump that delivers aconcentration of 40% macrocyclic lactone, such as Novolimus, with PBMAdissolved in dichloromethane solvent at a rate of 30 μl/min to thesurface of an ultrasonic nozzle, resulting in their atomization. Afterthe stent has linearly moved back and forth for a number of cycles, thecoating process is terminated when the coating weight is approximately450 μg PBMA:Novolimus. The stent is then placed in a vacuum for at 36hrs to evacuate residual solvents to less than 50 ppm.

Example 5 Stent with Polyethylene Carbonate Coating

A 0.011″ (0.27 mn) wire mandrel is bent 360 degrees forming a loop atthe apex. It is inserted into a surface treated stent from example 1which was precrimped to 0.036″ (0.91 mn) ID. The mandrel is thenattached to the sample holding fixture of Sono-Tek Micromist™ ultrasoniccoater such that the stent is rotated and moving back and forth beneathan ultrasonic nozzle. The coater has syringe pump that delivers aconcentration of 66% macrocyclic lactone with PEC dissolved indichloromethane solvent at a rate of 30 μl/min to the surface of anultrasonic nozzle, resulting in their atomization. After the stent haslinearly moved back and forth for a number of cycles, the coatingprocess is terminated when the coating weight is approximately 75 μgPEC:Macrocyclic lactone. The stent is then placed in a vacuum for at 36hrs to evacuate residual solvents to less than 50 ppm.

Example 6 Stent with PLLA-TMC Coating

A 0.011″ (0.27 mn) wire mandrel is bent 360 degrees forming a loop atthe apex. It is inserted into a surface treated stent from example 1which was precrimped to 0.036″ (0.91 mn) ID. The mandrel is thenattached to the sample holding fixture of Sono-Tek Micromist™ ultrasoniccoater such that the stent is rotated and moving back and forth beneathan ultrasonic nozzle. The coater has syringe pump that delivers aconcentration of 40% macrocyclic lactone (such as Novolimus) withPLLA-TMC dissolved in dichloromethane solvent at a rate of 30 μl/min tothe surface of an ultrasonic nozzle, resulting in their atomization.After the stent has linearly moved back and forth for a number ofcycles, the coating process is terminated when the coating weight isapproximately 450 μg PLLA-TMC:Macrocyclic lactone. The stent is thenplaced in a vacuum for at 36 hrs to evacuate residual solvents to lessthan 50 ppm.

Example 7 Stent Crimp Mounting and Expansion

The coated stent from either sample 4, 5, or 6 is inserted into a 0.046″(1.1 mn) inner diameter PTFE sheath. The folded nylon copolymer balloonon the distal end of a 20 mm long balloon stent delivery system isinserted into the stent lumen. The balloon is pressurized to 250 psiwhile the PTFE sheath surface is heated to about 35° C. above the Tg ofthe polymer coatings for about 30 seconds and then cooled. Aftercooling, the balloon may be depressurized. The PTFE sheath is removedfrom the stent, leaving a crimped stent on the balloon of the catheter.The stent delivery catheter may then be packaged and sterilized byethylene oxide. The stent is expanded under physiological conditionswith minimal to no cracking or smearing of the coating. FIGS. 5 and 6show light microscopy images of ID and OD of a PEC coated stent afterexpansion.

Example 8 In Vivo Testing of PBMA Coated Stent and PEC Coated Stent

Tissue and blood compatibility of PBMA coated and PEC coated stents wereevaluated in by comparing histomorphometry and pathology of the tissuearound the stents in a porcine coronary artery model after 28 and 90days of implantation. The stents were coated with PBMA (as in example 4)and PEC (as in example 5) but with polymer only without any drugcontent.

The nonatherosclerotic swine model was chosen as this model has beenused extensively for stent and angioplasty studies resulting in a largevolume of data on the vascular response properties and its correlationto human vascular response (Schwartz et al, Circulation. 2002;106:1867-1873). The animals were housed and cared for in accordance theGuide for the Care and Use of Laboratory Animals as established by theNational Research Council.

All animals were pretreated with aspirin 325 mg and clopidogel (75 mg)per oral beginning at least 3 days prior to the intervention andcontinuing for duration of the study. After induction of anesthesia, theleft or right femoral artery was accessed using standard techniques andan arterial sheath was introduced and advanced into the artery.

Vessel angiography was performed under fluoroscopic guidance, a 7 Fr.guide catheter was inserted through the sheath and advanced to theappropriate location; intracoronary nitroglycerin was administered. Asegment of coronary artery ranging from 2.25 to 4.0 mm mean lumendiameter was chosen and a 0.014″ (0.35 mm) guidewire inserted.Quantitative Coronary Angiography (QCA) was performed to document thereference vessel diameter.

The appropriately sized stent was advanced to the deployment site. Theballoon was inflated at a steady rate to a pressure sufficient toachieve a balloon to artery ratio of 1.1:1.0. Pressure was maintainedfor approximately 10 seconds. Angiography was performed to documentpost-procedural vessel patency and diameter.

Follow-up angiography was performed at the designated endpoint for eachof the animals. Each angiogram was qualitatively evaluated for evidenceof stent migration, lumen narrowing, stent apposition, presence ofdissection or aneurysms, and flow characteristics. Upon completion offollow-up angiography, the animals were euthanized.

The hearts were harvested from each animal and the coronary arterieswere perfused with 10% buffered formalin at 100 to 120 mm Hg. The heartswere immersed in 10% buffered formalin. Any myocardial lesions orunusual observations were reported.

Angiographic parameters measured or calculated included:

-   -   1. Marginal vessel (proximal and distal) mean lumen diameter        (post-stent and final)    -   2. Mean lumen diameter of the target region (all angiograms)    -   3. Minimal lumen diameter (MLD) of the target region (post-stent        and final only)    -   4. Diameter stenosis [1−(MLD/RVD)]×100%] where RVD is a        calculation of the reference diameter at the position of the        obstruction (measure obtained by a software-based iterative        linear regression technique to generate an intrapolation of a        projected vessel without the lesion) (final angiogram only).    -   5. Balloon to artery ratio [balloon/pre-stent mean luminal        diameter]    -   6. Stent to artery ratio [post-stent/pre-stent mean luminal        diameter]    -   7. Late loss ratio [MLD final-MLD post-stent]

All animal survived to the designated end point. There were nodocumented incidents of stent migration, stent malapposition, persistentdissection or evidence of aneurysm. At 28-days the three groups showedsimilar results in intimal area (mm²) of 1.44±0.58 vs. 1.64±0.82 vs.1.42±0.68 for PEC coated, PBMA coated and Bare Metal stent respectively(FIG. 7). Pathological examination for fibrin deposition, calcificationand endothelialization showed comparable results across all stents. At90-days the three groups showed similar results in intimal area (mm²) of1.92±0.8 vs. 2.61±0.7 vs. 1.79±0.9 for PEC coated, PBMA coated and BareMetal stent respectively (FIG. 8). Pathological examination for fibrindeposition, calcification and endothelialization showed comparableresults across all stents. PEC and PBMA coatings in this example showedcomparable biocompatibility to bare metal stents in an in vivo model.

Example 9 In Vivo Testing of PEC Drug Coated Stent

The efficacy of a PEC drug coated stent (as prepared above in Example 5)with 60-75 μg of PEC:macrocyclic lactone drug compound was evaluated bycomparing 28±2 day, 90±5 day, and 180±5 day histomorphometric outcomesin porcine coronary arteries to rapamycin eluting stent system, Cypher™coronary stent (Cordis Corporation) in the non-diseased porcine coronaryartery model. The interventional procedure is as described in Example 8;for the 28-day implant stent implantation was conducted at a higherballoon:artery ratio of 1.3:1.0 and for the 90-day and 180-day implants,stent implantation was conducted at the lower balloon:artery ratio of1.1:1.0.

28-day Implant: All animal survived to the designated end point. Therewere no documented incidents of stent migration, stent malapposition,persistent dissection or evidence of aneurysm. The average intimal area(mm²) for the PEC drug coated stent (approx. 2.5 μg/mm length drug dose)was 2.5±1.2 (n=15) as compared to the pooled Cypher™ stent data providedan average intimal area (mm²) of 2.5±0.9 (n=40). (FIG. 9).

The PEC drug coated stents in this example when implanted in the porcinemodel for 28 days resulted in similar neointimal formation as theCypher™ stent.

90-day Implant: All animals survived to the designated end point. Therewere no documented incidents of stent migration, stent malapposition,persistent dissection or evidence of aneurysm. The average intimal area(mm²) for the PEC drug coated stent (approx. 2.5 μg/mm length drug dose)was 2.50±0.9 (n=6) as compared to the implanted Cypher™ stent whichprovided an average intimal area (mm²) of 2.3.9±2.2 (n=20). (FIG. 10)

The PEC drug coated stents in this example when implanted in the porcinemodel for 90 days resulted in similar neointimal formation as theCypher™ stent.

180-day Implant: All but one animal survived to the designated endpoint. The animal that did not survive died at day 6 due to a thrombusformation caused by procedural issue of under dilation of a stent duringimplantation. There were no documented incidents of stent migration,stent malapposition, persistent dissection or evidence of aneurysm. Theaverage intimal area (mm²) for the PEC drug coated stent (approx. 4.4μg/mm length drug dose) was 1.98±0.7 (n=2) as compared to theconcurrently implanted Cypher™ stent provided an average intimal area(mm²) of 2.70±1.15 (n=2). (FIG. 11)

The PEC drug coated stents in this example when implanted in the porcinemodel for 180 days resulted in similar neointimal formation as theCypher™ stent.

Example 10 In Vivo Pharmacokinetics of PEC Drug Coated Stents

Pharmacokinetic evaluation of the PEC drug coated stent system fromExample 9 was performed at 6 hours, 3 days and 28 days in the porcinecoronary artery model.

The interventional procedures are similar to the in vivo angiographicstudy described in Example 8 up to stent implantation. The appropriatelysized stent was advanced to the deployment site. The balloon wasinflated at a steady rate to a pressure sufficient to achieve a balloonto artery ratio of 1:1. Pressure was maintained for approximately 10seconds. Angiography was performed to document post-procedural vesselpatency and diameter. A total of 9 stents (3 per time point) wereimplanted.

At the appropriate time point the animals were euthanized and the heartsexcised. The stented segment including approximately 10 mm of vesselproximal and 10 mm distal to the stented section was excised. Theproximal and distal sections were separated and stored in separatevials. The tissue surrounding the stent was carefully removed from stentand each place in separate vials. All were then frozen to −70° C. priorto being analyzed using high performance liquid chromatography (HPLC).

All animal survived to the designated end point. The stent and tissuepharmacokinetics for the PEC drug coated stent are presented in FIGS. 12and 13.

The PEC drug coated stent, in this example, demonstrates the releaseprofile of drug from the stent with approximately 90% of the drugreleased within 7 days with drug tissue concentrations present over atleast the same period.

Example 11 In Vivo Testing of PBMA Drug Coated Stent

The efficacy of a PBMA drug coated stent (as prepared above in Example4) with 450 μg of PBMA:Novolimus drug compound was evaluated bycomparing 28±2 day and 90±5 day histomorphometric outcomes in porcinecoronary arteries to rapamycin eluting stent system, Cypher™ coronarystent (Cordis Corporation) in the non-diseased porcine coronary arterymodel. The interventional procedure is as described in Example 8 butwith a higher balloon:artery ratio of 1.3:1.0 and for the 90-dayimplants, stent implantation was conducted at the lower balloon:arteryratio of 1.1:1.0.

28-day Implant: All animal survived to the designated end point. Therewere no documented incidents of stent migration, stent malapposition,persistent dissection or evidence of aneurysm. Three outlying datapoints (total occlusion or near total occlusion) for the Cypher™ stentwere excluded. The average intimal area (mm²) for the PBMA drug coatedstent (approx. 10 μg/mm length drug dose) was 2.0±0.5 (n=14) as comparedto Cypher™ stent pooled data from this and previous studies with similarprotocols which provided an average percent stenosis of 2.5±0.9 (n=40)for Cypher™ stents. (FIG. 14)

The PBMA drug coated stent in this example when implanted in the porcinemodel for 28 days resulted in similar neointimal formation as theCypher™ stent.

90-day Implant: All animal survived to the designated end point. Therewere no documented incidents of stent migration, stent malapposition,persistent dissection or evidence of aneurysm. Three outlying datapoints (total occlusion or near total occlusion) for the Cypher™ stentwere excluded. The average intimal area (mm²) for the PBMA drug coatedstent (approx. 10 μg/mm length drug dose) was 2.5±0.6 (n=6) as comparedto Cypher™ stent pooled data from this and previous studies with similarprotocols which provided an average percent stenosis of 3.9±2.2 (n=20)for Cypher™ stents. (FIG. 15)

The PBMA drug coated stent in this example when implanted in the porcinemodel for 90 days resulted in similar neointimal formation as theCypher™ stent.

Example 12 In Vivo Pharmacokinetics of PBMA Drug Coated Stents

Pharmacokinetic evaluation of the PBMA drug coated stent system fromExample 11 was performed at 6 hours, 3 days and 28 days in the porcinecoronary artery model

The interventional procedures are similar to the in vivo angiographicstudy described in Example 10. All animal survived to the designated endpoint. The stent and tissue pharmacokinetics for PBMA drug coated stentsFIGS. 16 and 17.

The PBMA drug coated stent, in this example demonstrates release of drugfrom the stent with approximately 50% of the drug released at 7 days andapproximately 70% at 28 days with drug tissue concentrations presentover at least a 14 day period.

Example 13 In Vivo Testing of PLLA-TMC Drug Coated Stent

The efficacy of a PLLA-TMC drug coated stent (as prepared above inExample 6) with 75 μg of PLLA-TMC drug compound was evaluated bycomparing 28±2 day angiographic outcomes in porcine coronary arteries torapamycin eluting stent system, Cypher™ coronary stent (CordisCorporation) in the non-diseased porcine coronary artery model. Theinterventional procedure is as described in Example 8; for the 28-dayimplant stent implantation was conducted at a higher balloon:arteryratio of 1.3:1.0

All animal survived to the designated end point. There were nodocumented incidents of stent migration, stent malapposition, persistentdissection or evidence of aneurysm. The average intimal area (mm²) forthe PLLA-TMC drug coated stent (approx. 2.7 μg/mm length drug dose) was2.3±0.9 (n=8) as compared to the Cypher™ stent provided an averageintimal area (mm²) of 2.5±0.9 (n=40). (FIG. 18)

The PEC drug coated stents in this example when implanted in the porcinemodel for 28 days resulted in similar neointimal formation as theCypher™ stent.

Example 14 In Vivo Pharmacokinetics of PLLA-TMC Drug Coated Stents

Pharmacokinetic evaluation of the PEC drug coated stent system fromExample 6 was performed at 6 hours, 3 days and 28 days in the porcinecoronary artery model

The interventional procedures are similar to the in vivo angiographicstudy described in Example 8 up to stent implantation. The appropriatelysized stent was advanced to the deployment site. The balloon wasinflated at a steady rate to a pressure sufficient to achieve a balloonto artery ratio of 1:1. Pressure was maintained for approximately 10seconds. Angiography was performed to document post-procedural vesselpatency and diameter. A total of 9 stents (3 per time point) wereimplanted.

At the appropriate time point the animals were euthanized and the heartsexcised. The stented segment including approximately 10 mm of vesselproximal and 10 mm distal to the stented section was excised. Theproximal and distal sections were separated and stored in separatevials. The tissue surrounding the stent was carefully removed from stentand each place in separate vials. All were then frozen to −70° C. priorto being analyzed using high performance liquid chromatography (HPLC).

All animal survived to the designated end point. The stent and tissuepharmacokinetics for the PLLA-TMC drug coated stent are presented inFIGS. 19 and 20.

The PLLA-TMC drug coated stent, in this example, demonstrates therelease profile of drug from the stent with approximately 90% of thedrug released within 7 days with drug tissue concentrations present overat least the same period.

Those skilled in the art will recognize that the present invention maybe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail may be made without departing from the scope and spirit of thepresent invention as described in the appended claims.

What is claimed is:
 1. A luminal prosthesis comprising: a scaffoldadapted to be radially deformed in a body lumen, said scaffold having anouter surface region and undergoing strain when the scaffold isdeformed, wherein the surface region is modified; and a coatingdeposited over the surface region, wherein the coating interacts withthe modified surface region to have an adherence greater than adherencein the absence of the surface modification.